Tuberculosis, MeningealPhase 1/2TBM-KIDSNCT02958709
Optimizing Treatment to Improve TBM Outcomes in Children
A Phase 1/2 study testing High-dose: RIF, INH, PZA, EMB and High dose: RIF, INH, PZA, LEVO in people with Tuberculosis, Meningeal, run by Johns Hopkins University at 3 sites in 2 countries.
Trial summary
In this open-labeled, randomized clinical trial, the Investigator will assess the safety and pharmacokinetics (PK) of model-optimized doses of rifampicin (RIF) with or without levofloxacin (LEVO) given to children as part of multidrug treatment for tuberculous meningitis (TBM) versus standard treatment. Read more about this study
- Who is it for?
- Ages 6 months to 12 years
- Conditions the study is for
- Tuberculosis, Meningeal
- What is being tested?
- High-dose: RIF, INH, PZA, EMB and High dose: RIF, INH, PZA, LEVO
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 38 participants
- Where
- 3 sitesin 2 countries
- Study dates
- 22 Feb 2017to 15 Nov 2020
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 6 months to 12 years
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- Weight > 6kg
- Age ≥ 6 months to < 12 years and, in the opinion of the investigator, can tolerate the treatment and study participation.
- Probable or definite TBM according to diagnostic criteria or a positive Gene Xpert cerebrospinal fluid (CSF) test.
- Since participants will all be under legal age of independent consent, a parent or legal guardian must be willing and able to provide informed consent. If the subject is of appropriate age, she/he will also be asked to give assent if developmentally appropriate and clinically possible.
- Participant can comply with the protocol requirements in the opinion of the site investigator.
Who cannot join
- TB treatment for > 7 days
- Exposure via close contact with someone with multi drug resistant TB (MDR-TB) (or rifampicin mono-resistant TB) or personal history of MDR-TB (or rifampicin mono-resistant TB)
- Known intolerance or allergy to any of the study drugs
- Death imminent and expected within 24 hours, as assessed by the site investigator
- Moderate to severe renal or liver dysfunction (Grade 2 or higher abnormalities of creatinine, alanine aminotransferase (ALT), or direct bilirubin)
- HIV infection with any of the following:
Show all 10Show fewer
- Planned initiation of antiretroviral treatment (ART) during the experimental treatment phase (first 8 weeks), as initiation of ART is contraindicated in that time period with TBM.
- On ART with planned continued use of a protease inhibitor or nevirapine (children can be switched to an acceptable alternative regimen and then participate)
- Having participated in other clinical studies with investigational agents or treatments within 8 weeks prior to enrollment.
- A clinically significant active medical condition or the presence of any concomitant severe illness or rapidly deteriorating health condition (outside of TB), which, in the opinion of the site investigator, would prevent appropriate participation in the trial, or that would make implementation of the protocol or interpretation of the study results difficult, or otherwise make the subject a poor candidate for a clinical trial.
Trial locations and contacts
3 sites in 2 countries.
3 sites in 2 countries
India2 sites
National Institute of Research in TB and Institute of Child Health
Chennai, Tamil Nadu, 600031
Byramji Jeejeebhoy Government Medical College and Sassoon Hospital
Pune, Maharashtra, 411001
About this study
Official title: Phase I/II Randomized, Open-label Trial to Evaluate the PK, Safety, and Outcomes of Treatment Including High Dose Rifampicin +/- Levofloxacin vs Standard Treatment for Pediatric Tuberculous Meningitis (TBM)
In this open-labeled, randomized clinical trial, the Investigator will assess the safety and pharmacokinetics (PK) of model-optimized doses of rifampicin (RIF) with or without levofloxacin (LEVO) given to children as part of multidrug treatment for tuberculous meningitis (TBM) versus standard treatment. The Investigators will also assess functional and neurocognitive outcomes by treatment group, as measured by the Pediatric Modified Rankin Score (MRS) and the Mullen Scales of Early Learning (MSEL), respectively.
Read the detailed description
Open-label, randomized clinical trial in three treatment groups. Patients with probable or definite TB meningitis (TBM) will all receive isoniazid and pyrazinamide at standard doses for 8 weeks. Arm 1 participants will receive high-dose rifampicin plus ethambutol (EMB) at standard doses for 8 weeks. Arm 2 participants will receive high-dose rifampicin plus levofloxacin for 8 weeks. Arm 3 participants will receive rifampicin plus ethambutol at standard doses for 8 weeks (control arm). Patients will be screened to confirm TBM diagnosis, will receive 8 weeks of study treatment, and then will receive isoniazid (INH)/rifampicin for an additional 40 weeks, to complete 12 months of TBM treatment. All participants will receive oral steroids. PK sampling will be performed within first week and 6 (+/- 2) weeks following treatment initiation. Participants will have scheduled follow-up visits to assess safety and clinical status. In addition, functional and neurocognitive outcomes up to 18 months following treatment initiation will be assessed. Interim PK and safety analyses will be performed to ensure dosing is producing predefined PK targets and safety is acceptable. It is anticipated that a majority of children will be hospitalized for the initial 2-8 weeks of the study.
- Conditions
- Tuberculosis, Meningeal
- Being tested
- High-dose: RIF, INH, PZA, EMB, High dose: RIF, INH, PZA, LEVO, Standard of care: RIF, INH, PZA, EMB
- Medical subject headings
- Tuberculosis, Meningeal
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
High-dose: RIF, INH, PZA, EMBDrug
Also called Rifampin
high-dose rifampicin plus standard dose H,Z,E, given for 8 weeks in treatment Arms 1 and 2
High dose: RIF, INH, PZA, LEVODrug
Also called Levaquin
high-dose rifampicin plus standard dose H,Z, with levofloxacin substituted for ethambutol for 8 weeks in treatment Arm 2
Standard of care: RIF, INH, PZA, EMBDrug
Also called control group
standard doses of R,H,Z,E given for 8 weeks in treatment Arm 3, control arm.
| Study group | Role | What they receive |
|---|---|---|
| high dose RIF, INH, PZA, EMB | Experimental | Arm 1 participants will receive high-dose rifampicin for 8 weeks plus ethambutol at standard doses, in addition to standard doze pyrazinamide (PZA) and isoniazid. Receives: Drug: High-dose: RIF, INH, PZA, EMB |
| high dose RIF, INH, PZA, LEVO | Experimental | Arm 2 participants will receive high-dose rifampicin plus levofloxacin for 8 weeks, in addition to standard doze pyrazinamide and isoniazid. Receives: Drug: High dose: RIF, INH, PZA, LEVO |
| standard dose RIF, INH, PZA, EMB | Active comparator | Arm 3 participants will receive standard of care dose rifampicin plus ethambutol for 8 weeks, in addition to standard doze pyrazinamide and isoniazid. Receives: Drug: Standard of care: RIF, INH, PZA, EMB |
What is being measured
The primary outcome is the main question the study is designed to answer.
Characterize the Volume of Distribution (Vd) in plasma of rifampicin given at model-derived optimal daily doses in children ages 6 months to 12 years of age with TBM.
Apparent volume of distribution estimated using population PK model
Measured: Weeks 1-16
Characterize the Oral Clearance (CL/F) in plasma of rifampicin given at model-derived optimal daily doses in children ages 6 months to 12 years of age with TBM.
Examines the apparent total clearance of rifampicin from plasma after oral administration.
Unit of Measure: Volume/time or volume/time/kg
Measured: Weeks 1-16
Characterize the Rate of Absorption (ka) in plasma of rifampicin given at model-derived optimal daily doses in children ages 6 months to 12 years of age with TBM.
Examines the absorption rate constant for orally administered rifampicin. Unit of Measure: will be represented as a decimal.
Measured: Weeks 1-16
Characterize the Penetration Coefficient in CSF of rifampicin given at model-derived optimal daily doses in children ages 6 months to 12 years of age with TBM.
Examines the ratio of CSF concentration to Plasma concentration of rifampicin Unit of Measure: will be represented as a decimal
Measured: Weeks 1 and 6
Characterize the Volume of Distribution (Vd) in plasma of levofloxacin given at model-derived optimal daily doses in children ages 6 months to 12 years of age with TBM.
Examines the apparent volume in which levofloxacin is distributed (i.e., the parameter relating drug concentration to drug amount in the body).
Unit of measure: Liter (L)
Measured: Weeks 1-16
Characterize the Volume of Distribution (Vd) in plasma of levofloxacin given at model-derived optimal daily doses in children ages 6 months to 12 years of age with TBM.
Examines the apparent volume in which levofloxacin is distributed (i.e., the parameter relating drug concentration to drug amount in the body).
Unit of measure: Liter (L)
Measured: Week 4
Characterize the Volume of Distribution (Vd) in plasma of levofloxacin given at model-derived optimal daily doses in children ages 6 months to 12 years of age with TBM.
Examines the apparent volume in which levofloxacin is distributed (i.e., the parameter relating drug concentration to drug amount in the body).
Unit of measure: Liter (L)
Measured: Week 8
Characterize the Volume of Distribution (Vd) in plasma of levofloxacin given at model-derived optimal daily doses in children ages 6 months to 12 years of age with TBM.
Examines the apparent volume in which levofloxacin is distributed (i.e., the parameter relating drug concentration to drug amount in the body).
Unit of measure: Liter (L)
Measured: Week 16
Characterize the Oral Clearance (CL/F) in plasma of levofloxacin given at model-derived optimal daily doses in children ages 6 months to 12 years of age with TBM.
Examines the apparent total clearance of levofloxacin from plasma after oral administration.
Unit of Measure: Volume/time or volume/time/kg
Measured: Weeks 1-16
Characterize the Oral Clearance (CL/F) in plasma of levofloxacin given at model-derived optimal daily doses in children ages 6 months to 12 years of age with TBM.
Examines the apparent total clearance of levofloxacin from plasma after oral administration.
Unit of Measure: Volume/time or volume/time/kg
Measured: Week 4
Characterize the Oral Clearance (CL/F) in plasma of levofloxacin given at model-derived optimal daily doses in children ages 6 months to 12 years of age with TBM.
Examines the apparent total clearance of levofloxacin from plasma after oral administration.
Unit of Measure: Volume/time or volume/time/kg
Measured: Week 8
Characterize the Rate of Absorption (ka) in plasma of levofloxacin given at model-derived optimal daily doses in children ages 6 months to 12 years of age with TBM.
Examines the absorption rate constant for orally administered levofloxacin. Unit of Measure: will be represented as a decimal.
Measured: Weeks 1-16
Characterize the Rate of Absorption (ka) in plasma of levofloxacin given at model-derived optimal daily doses in children ages 6 months to 12 years of age with TBM.
Examines the absorption rate constant for orally administered levofloxacin. Unit of Measure: will be represented as a decimal.
Measured: Week 4
Characterize the Rate of Absorption (ka) in plasma of levofloxacin given at model-derived optimal daily doses in children ages 6 months to 12 years of age with TBM.
Examines the absorption rate constant for orally administered levofloxacin. Unit of Measure: will be represented as a decimal.
Measured: Week 16
Characterize the Penetration Coefficient in CSF of levofloxacin given at model-derived optimal daily doses in children ages 6 months to 12 years of age with TBM.
Examines the ratio of CSF to Plasma concentration of levofloxacin Unit of Measure: will be represented as a decimal
Measured: Weeks 1 and 6
Assess the relationship between RIF concentrations and longitudinal functional outcomes as measured by longitudinal Modified Rankin Score (MRS) for children
At the end of treatment, all participants' RIF concentrations (Cmax and AUC) will be compared across time against their MRS scores. MRS parameters and their scores (in parentheses) as follows: No symptoms at all (0),No significant disabilities despite symptoms in clinical examination; age appropriate behaviour and further development (1),Slight disability; unable to carry out all previous activities, but same independence as other age- and sex-matched children (no reduction of levels on the gross motor function scale) (2),Moderate disability; requiring some help, but able to walk without assistance; in younger patients adequate motor development despite mild functional impairment (reduction of one level on the gross motor function scale) (3), Moderately severe disability; unable to walk without assistance; in younger patients reduction of at least 2 levels on the gross motor function scale (4),Severe disability; bedridden, requiring constant nursing care and attention (5),
Measured: 48 weeks
To evaluate the safety of TBM treatment over eight weeks, by treatment Arm, as measured by Grade 3 or higher adverse events
Grade 3 Adverse Events as defined by the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events
Measured: 8 weeks
Secondary outcomes (6)
Describe neurocognitive outcomes among children ages 6 months to 6 years of age who are treated for TBM, longitudinally over 18 months, by treatmentArm, as measured by the Mullen Gross Motor Scale
The Gross Motor Scale is used to assess infants who are 33 months of age or younger and provides information about the child's kinesthetic experience.
Maximum Raw Scores of Gross Motor Scale: 36 Raw scores are converted to T Scores (A type of standardized score) based on the child's age.
A T Score has a mean of 50 and a standard deviation of 10. A T Score between 20 and 30 (or less than 20) has a descriptive category of "Very Low" A T Score between 31 and 39 has a descriptive category of "Below Average" A T Score between 40 and 60 has a descriptive category of "Average" A T Score between 61 and 69 has a descriptive category of "Above Average" A T Score between 70 and 80 has a descriptive category of "Very High"
Measured: 72 weeks
Describe neurocognitive outcomes among children ages 6 months to 6 years of age who are treated for TBM, longitudinally over 18 months, by treatmentArm, as measured by the Mullen Visual Reception Scale
A cognitive score that may be derived from children ages birth to 68 months of age.
The Visual Reception Scale assesses visual processing skills through isolation of oculomotor and visual-motor operations. This scale minimizes the motor output required to execute the response and eliminates the need for verbalized responses.
Maximum Raw Scores of the Visual Reception Scale: 50 Raw scores are converted to T Scores (A type of standardized score) based on the child's age.
A T Score has a mean of 50 and a standard deviation of 10. A T Score between 20 and 30 (or less than 20) has a descriptive category of "Very Low" A T Score between 31 and 39 has a descriptive category of "Below Average" A T Score between 40 and 60 has a descriptive category of "Average" A T Score between 61 and 69 has a descriptive category of "Above Average" A T Score between 70 and 80 has a descriptive category of "Very High"
Measured: Week 72
Describe neurocognitive outcomes among children ages 6 months to 6 years of age who are treated for TBM, longitudinally over 18 months, by treatmentArm, as measured by the Mullen Fine Motor Scale
A cognitive score that may be derived from children ages birth to 68 months of age.
The Fine Motor Scale emphasizes the output aspect of visual organization by assessing visual-motor skills, such as motor planning, motor control, and writing readiness.
Maximum Raw Scores of the Fine Motor Scale: 49 Raw scores are converted to T Scores (A type of standardized score) based on the child's age.
A T Score has a mean of 50 and a standard deviation of 10. A T Score between 20 and 30 (or less than 20) has a descriptive category of "Very Low" A T Score between 31 and 39 has a descriptive category of "Below Average" A T Score between 40 and 60 has a descriptive category of "Average" A T Score between 61 and 69 has a descriptive category of "Above Average" A T Score between 70 and 80 has a descriptive category of "Very High"
Measured: Week 72
Describe neurocognitive outcomes among children ages 6 months to 6 years of age who are treated for TBM, longitudinally over 18 months, by treatmentArm, as measured by the Mullen Receptive Language Scale
A cognitive score that may be derived from children ages birth to 68 months of age.
The Receptive Language Scale evaluates the ability to decode verbal input through tasks requiring auditory discrimination, linguistic conceptualization, sequencing, and use of spatial concepts.
Maximum Raw Scores of the Fine Motor Scale: 48 Raw scores are converted to T Scores (A type of standardized score) based on the child's age.
A T Score has a mean of 50 and a standard deviation of 10. A T Score between 20 and 30 (or less than 20) has a descriptive category of "Very Low" A T Score between 31 and 39 has a descriptive category of "Below Average" A T Score between 40 and 60 has a descriptive category of "Average" A T Score between 61 and 69 has a descriptive category of "Above Average" A T Score between 70 and 80 has a descriptive category of "Very High"
Measured: Week 72
Describe neurocognitive outcomes among children ages 6 months to 6 years of age who are treated for TBM, longitudinally over 18 months, by treatmentArm, as measured by the Mullen Expressive Language Scale
A cognitive score that may be derived from children ages birth to 68 months of age.
The Expressive Language Scale focuses on the child's use of spoken language for communication and expression during spontaneous utterances and during specific vocal or verbal responses to tasks.
Maximum Raw Scores of the Fine Motor Scale: 50 Raw scores are converted to T Scores (A type of standardized score) based on the child's age.
A T Score has a mean of 50 and a standard deviation of 10. A T Score between 20 and 30 (or less than 20) has a descriptive category of "Very Low" A T Score between 31 and 39 has a descriptive category of "Below Average" A T Score between 40 and 60 has a descriptive category of "Average" A T Score between 61 and 69 has a descriptive category of "Above Average" A T Score between 70 and 80 has a descriptive category of "Very High"
Measured: Week 72
Describe TBM treatment outcomes at 12 months which will be classified as favorable (cured or treatment completed) or unfavorable (death, lost to follow up, treatment failure, transferred out) at 48 weeks.
TB treatment outcomes , favorable or unfavorable
Measured: 48 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Nov 2016 (estimated)
- Study start22 Feb 2017
- Primary completion15 Nov 2020
- Study completion15 Nov 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Tuberculosis, MeningealStudies of the same condition, open and under way.
- More trials run by Johns Hopkins UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 38 participants (actual)
Sponsor and investigators
- Lead sponsor
- Johns Hopkins University
- Sponsor type
- University, hospital or other
- Collaborators
- National Institute for Research in Tuberculosis, Chennai, India, University of North Carolina, B. J. Medical College, Pune, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
- Responsible party
- Sponsor
- Investigators
- Kelly Dooley, MD,PhD, Principal investigator, Johns Hopkins University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02958709
- Sponsor's protocol ID
- IRB00051196
- Other IDs
- 1R01HD074944-01A1
- Acronym
- TBM-KIDS
- Status last verified
- Aug 2020
- First submitted
- 13 Sep 2016
- Last updated
- 28 Oct 2021
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Paradkar MS, Devaleenal D B, Mvalo T, Arenivas A, Thakur KT, Wolf L, Nimkar S, Inamdar S, Giridharan P, Selladurai E, Kinikar A, Valvi C, Khwaja S, Gadama D, Balaji S, Yadav Kattagoni K, Venkatesan M, Savic R, Swaminathan S, Gupta A, Gupte N, Mave V, Dooley KE; TuBerculous Meningitis in Kids (TBM-KIDS) Study Team. Randomized Clinical Trial of High-Dose Rifampicin With or Without Levofloxacin Versus Standard of Care for Pediatric Tuberculous Meningitis: The TBM-KIDS Trial. Clin Infect Dis. 2022 Oct 29;75(9):1594-1601. doi: 10.1093/cid/ciac208.
PubMed 35291004
Study at a glance
From the registry record, last updated by the sponsor on 28 Oct 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase I/II Randomized, Open-label Trial to Evaluate the PK, Safety, and Outcomes of Treatment Including High Dose Rifampicin +/- Levofloxacin vs Standard Treatment for Pediatric Tuberculous Meningitis (TBM)
- ClinicalTrials.gov ID
- NCT02958709
- Acronym / sponsor ID
- TBM-KIDS / IRB00051196
- Conditions
- Tuberculosis, Meningeal
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 38 participants (actual)
- Lead sponsor
- Johns Hopkins UniversityUniversity, hospital or other
- Collaborators
- National Institute for Research in Tuberculosis, Chennai, India, University of North Carolina, B. J. Medical College, Pune, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
- Study start
- 22 Feb 2017 (actual)
- Primary completion
- 15 Nov 2020 (actual)
- Study completion
- 15 Nov 2020 (actual)
- First posted
- 8 Nov 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
In this open-labeled, randomized clinical trial, the Investigator will assess the safety and pharmacokinetics (PK) of model-optimized doses of rifampicin (RIF) with or without levofloxacin (LEVO) given to children as part of multidrug treatment for tuberculous meningitis (TBM) versus standard treatment. The Investigators will also assess functional and neurocognitive outcomes by treatment group, as measured by the Pediatric Modified Rankin Score (MRS) and the Mullen Scales of Early Learning (MSEL), respectively.
Detailed description
Open-label, randomized clinical trial in three treatment groups. Patients with probable or definite TB meningitis (TBM) will all receive isoniazid and pyrazinamide at standard doses for 8 weeks. Arm 1 participants will receive high-dose rifampicin plus ethambutol (EMB) at standard doses for 8 weeks. Arm 2 participants will receive high-dose rifampicin plus levofloxacin for 8 weeks. Arm 3 participants will receive rifampicin plus ethambutol at standard doses for 8 weeks (control arm). Patients will be screened to confirm TBM diagnosis, will receive 8 weeks of study treatment, and then will receive isoniazid (INH)/rifampicin for an additional 40 weeks, to complete 12 months of TBM treatment. All participants will receive oral steroids. PK sampling will be performed within first week and 6 (+/- 2) weeks following treatment initiation. Participants will have scheduled follow-up visits to assess safety and clinical status. In addition, functional and neurocognitive outcomes up to 18 months following treatment initiation will be assessed. Interim PK and safety analyses will be performed to ensure dosing is producing predefined PK targets and safety is acceptable. It is anticipated that a majority of children will be hospitalized for the initial 2-8 weeks of the study.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| high dose RIF, INH, PZA, EMB | Experimental | Drug: High-dose: RIF, INH, PZA, EMBArm 1 participants will receive high-dose rifampicin for 8 weeks plus ethambutol at standard doses, in addition to standard doze pyrazinamide (PZA) and isoniazid. |
| high dose RIF, INH, PZA, LEVO | Experimental | Drug: High dose: RIF, INH, PZA, LEVOArm 2 participants will receive high-dose rifampicin plus levofloxacin for 8 weeks, in addition to standard doze pyrazinamide and isoniazid. |
| standard dose RIF, INH, PZA, EMB | Active comparator | Drug: Standard of care: RIF, INH, PZA, EMBArm 3 participants will receive standard of care dose rifampicin plus ethambutol for 8 weeks, in addition to standard doze pyrazinamide and isoniazid. |
Who may qualify
- Ages
- 6 months to 12 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (5 listed)
- Weight > 6kg
- Age ≥ 6 months to < 12 years and, in the opinion of the investigator, can tolerate the treatment and study participation.
- Probable or definite TBM according to diagnostic criteria or a positive Gene Xpert cerebrospinal fluid (CSF) test.
- Since participants will all be under legal age of independent consent, a parent or legal guardian must be willing and able to provide informed consent. If the subject is of appropriate age, she/he will also be asked to give assent if developmentally appropriate and clinically possible.
- Participant can comply with the protocol requirements in the opinion of the site investigator.
Key exclusion criteria (10 listed)
- TB treatment for > 7 days
- Exposure via close contact with someone with multi drug resistant TB (MDR-TB) (or rifampicin mono-resistant TB) or personal history of MDR-TB (or rifampicin mono-resistant TB)
- Known intolerance or allergy to any of the study drugs
- Death imminent and expected within 24 hours, as assessed by the site investigator
- Moderate to severe renal or liver dysfunction (Grade 2 or higher abnormalities of creatinine, alanine aminotransferase (ALT), or direct bilirubin)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| High-dose: RIF, INH, PZA, EMBAlso: Rifampinhigh-dose rifampicin plus standard dose H,Z,E, given for 8 weeks in treatment Arms 1 and 2 | Drug | high dose RIF, INH, PZA, EMB |
| High dose: RIF, INH, PZA, LEVOAlso: Levaquinhigh-dose rifampicin plus standard dose H,Z, with levofloxacin substituted for ethambutol for 8 weeks in treatment Arm 2 | Drug | high dose RIF, INH, PZA, LEVO |
| Standard of care: RIF, INH, PZA, EMBAlso: control groupstandard doses of R,H,Z,E given for 8 weeks in treatment Arm 3, control arm. | Drug | standard dose RIF, INH, PZA, EMB |
Primary outcome
Characterize the Volume of Distribution (Vd) in plasma of rifampicin given at model-derived optimal daily doses in children ages 6 months to 12 years of age with TBM.
Time frame: Weeks 1-16
Apparent volume of distribution estimated using population PK model
Characterize the Oral Clearance (CL/F) in plasma of rifampicin given at model-derived optimal daily doses in children ages 6 months to 12 years of age with TBM.
Time frame: Weeks 1-16
Examines the apparent total clearance of rifampicin from plasma after oral administration. Unit of Measure: Volume/time or volume/time/kg
Characterize the Rate of Absorption (ka) in plasma of rifampicin given at model-derived optimal daily doses in children ages 6 months to 12 years of age with TBM.
Time frame: Weeks 1-16
Examines the absorption rate constant for orally administered rifampicin. Unit of Measure: will be represented as a decimal.
Characterize the Penetration Coefficient in CSF of rifampicin given at model-derived optimal daily doses in children ages 6 months to 12 years of age with TBM.
Time frame: Weeks 1 and 6
Examines the ratio of CSF concentration to Plasma concentration of rifampicin Unit of Measure: will be represented as a decimal
Characterize the Volume of Distribution (Vd) in plasma of levofloxacin given at model-derived optimal daily doses in children ages 6 months to 12 years of age with TBM.
Time frame: Weeks 1-16
Examines the apparent volume in which levofloxacin is distributed (i.e., the parameter relating drug concentration to drug amount in the body). Unit of measure: Liter (L)
Characterize the Volume of Distribution (Vd) in plasma of levofloxacin given at model-derived optimal daily doses in children ages 6 months to 12 years of age with TBM.
Time frame: Week 4
Examines the apparent volume in which levofloxacin is distributed (i.e., the parameter relating drug concentration to drug amount in the body). Unit of measure: Liter (L)
Characterize the Volume of Distribution (Vd) in plasma of levofloxacin given at model-derived optimal daily doses in children ages 6 months to 12 years of age with TBM.
Time frame: Week 8
Examines the apparent volume in which levofloxacin is distributed (i.e., the parameter relating drug concentration to drug amount in the body). Unit of measure: Liter (L)
Characterize the Volume of Distribution (Vd) in plasma of levofloxacin given at model-derived optimal daily doses in children ages 6 months to 12 years of age with TBM.
Time frame: Week 16
Examines the apparent volume in which levofloxacin is distributed (i.e., the parameter relating drug concentration to drug amount in the body). Unit of measure: Liter (L)
Characterize the Oral Clearance (CL/F) in plasma of levofloxacin given at model-derived optimal daily doses in children ages 6 months to 12 years of age with TBM.
Time frame: Weeks 1-16
Examines the apparent total clearance of levofloxacin from plasma after oral administration. Unit of Measure: Volume/time or volume/time/kg
Characterize the Oral Clearance (CL/F) in plasma of levofloxacin given at model-derived optimal daily doses in children ages 6 months to 12 years of age with TBM.
Time frame: Week 4
Examines the apparent total clearance of levofloxacin from plasma after oral administration. Unit of Measure: Volume/time or volume/time/kg
Characterize the Oral Clearance (CL/F) in plasma of levofloxacin given at model-derived optimal daily doses in children ages 6 months to 12 years of age with TBM.
Time frame: Week 8
Examines the apparent total clearance of levofloxacin from plasma after oral administration. Unit of Measure: Volume/time or volume/time/kg
Characterize the Rate of Absorption (ka) in plasma of levofloxacin given at model-derived optimal daily doses in children ages 6 months to 12 years of age with TBM.
Time frame: Weeks 1-16
Examines the absorption rate constant for orally administered levofloxacin. Unit of Measure: will be represented as a decimal.
Characterize the Rate of Absorption (ka) in plasma of levofloxacin given at model-derived optimal daily doses in children ages 6 months to 12 years of age with TBM.
Time frame: Week 4
Examines the absorption rate constant for orally administered levofloxacin. Unit of Measure: will be represented as a decimal.
Characterize the Rate of Absorption (ka) in plasma of levofloxacin given at model-derived optimal daily doses in children ages 6 months to 12 years of age with TBM.
Time frame: Week 16
Examines the absorption rate constant for orally administered levofloxacin. Unit of Measure: will be represented as a decimal.
Characterize the Penetration Coefficient in CSF of levofloxacin given at model-derived optimal daily doses in children ages 6 months to 12 years of age with TBM.
Time frame: Weeks 1 and 6
Examines the ratio of CSF to Plasma concentration of levofloxacin Unit of Measure: will be represented as a decimal
Assess the relationship between RIF concentrations and longitudinal functional outcomes as measured by longitudinal Modified Rankin Score (MRS) for children
Time frame: 48 weeks
At the end of treatment, all participants' RIF concentrations (Cmax and AUC) will be compared across time against their MRS scores. MRS parameters and their scores (in parentheses) as follows: No symptoms at all (0),No significant disabilities despite symptoms in clinical examination; age appropriate behaviour and further development (1),Slight disability; unable to carry out all previous activities, but same independence as other age- and sex-matched children (no reduction of levels on the gross motor function scale) (2),Moderate disability; requiring some help, but able to walk without assistance; in younger patients adequate motor development despite mild functional impairment (reduction of one level on the gross motor function scale) (3), Moderately severe disability; unable to walk without assistance; in younger patients reduction of at least 2 levels on the gross motor function scale (4),Severe disability; bedridden, requiring constant nursing care and attention (5),
To evaluate the safety of TBM treatment over eight weeks, by treatment Arm, as measured by Grade 3 or higher adverse events
Time frame: 8 weeks
Grade 3 Adverse Events as defined by the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events
6 secondary outcomes
Describe neurocognitive outcomes among children ages 6 months to 6 years of age who are treated for TBM, longitudinally over 18 months, by treatmentArm, as measured by the Mullen Gross Motor Scale
Time frame: 72 weeks
Describe neurocognitive outcomes among children ages 6 months to 6 years of age who are treated for TBM, longitudinally over 18 months, by treatmentArm, as measured by the Mullen Visual Reception Scale
Time frame: Week 72
Describe neurocognitive outcomes among children ages 6 months to 6 years of age who are treated for TBM, longitudinally over 18 months, by treatmentArm, as measured by the Mullen Fine Motor Scale
Time frame: Week 72
Describe neurocognitive outcomes among children ages 6 months to 6 years of age who are treated for TBM, longitudinally over 18 months, by treatmentArm, as measured by the Mullen Receptive Language Scale
Time frame: Week 72
Describe neurocognitive outcomes among children ages 6 months to 6 years of age who are treated for TBM, longitudinally over 18 months, by treatmentArm, as measured by the Mullen Expressive Language Scale
Time frame: Week 72
Describe TBM treatment outcomes at 12 months which will be classified as favorable (cured or treatment completed) or unfavorable (death, lost to follow up, treatment failure, transferred out) at 48 weeks.
Time frame: 48 weeks
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Oct 2021.
- Derived from this study: PubMed 35291004Paradkar MS, Devaleenal D B, Mvalo T, Arenivas A, Thakur KT, Wolf L, Nimkar S, Inamdar S, Giridharan P, Selladurai E, Kinikar A, Valvi C, Khwaja S, Gadama D, Balaji S, Yadav Kattagoni K, Venkatesan M, Savic R, Swaminathan S, Gupta A, Gupte N, Mave V, Dooley KE; TuBerculous Meningitis in Kids (TBM-KIDS) Study Team. Randomized Clinical Trial of High-Dose Rifampicin With or Without Levofloxacin Versus Standard of Care for Pediatric Tuberculous Meningitis: The TBM-KIDS Trial. Clin Infect Dis. 2022 Oct 29;75(9):1594-1601. doi: 10.1093/cid/ciac208.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Kelly Dooley, MD,PhD principal investigator
Johns Hopkins University
3 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing High-dose: RIF, INH, PZA, EMB and High dose: RIF, INH, PZA, LEVO in people with Tuberculosis, Meningeal, run by Johns Hopkins University at 3 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 28 Oct 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in India, Malawi. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Characterize the Volume of Distribution (Vd) in plasma of rifampicin given at model-derived optimal daily doses in children ages 6 months to 12 years of age with TBM. (time frame: Weeks 1-16). The study lists 17 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02958709, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Oct 2021.